Benzophenone Compounds, from a Marine-Derived Strain of the Fungus <i>Pestalotiopsis neglecta</i>, Inhibit Proliferation of Pancreatic Cancer Cells by Targeting the MEK/ERK Pathway

Pancreatic cancer, which has an extremely poor prognosis, is one of the most fatal human cancers. Chemotherapy is the main palliative treatment for advanced cancer patients and also plays an indispensable role in postoperative treatments for surgical patients. Therefore, there is an urgent need to develop more innovative anticancer drugs to fight against this fatal disease. Here, we investigate the potential of benzophenone derivatives, obtained from a marine-derived strain of the fungus Pestalotiopsis neglecta, as antiproliferative lead compounds for the treatment of pancreatic cancer. The compounds, seven new (1–7) and two known (8 and 9) halogenated benzophenone derivatives, were obtained by bioactivity-guided fractionation from the cultures of Pestalotiopsis neglecta. The structures were defined by spectroscopic methods including X-ray crystallographic analysis. Using the commonly used pancreatic cancer cell line PANC-1, 2 and 4 were found to suppress cell proliferation and induce apoptosis in the low micromolar range of 7.6 and 7.2 μM, respectively. Mechanistically, benzophenone derivatives not only inhibit MEK activity in the cytoplasm but also suppress ERK activity in the cytoplasm and nucleus. An in silico study suggests that benzophenone derivatives could potentially inhibit MEK activity by binding to the allosteric pocket in MEK. Benzophenones could serve as new lead compounds for the treatment of pancreatic cancer.预后极差的胰腺癌是人类致死率最高的恶性肿瘤之一。化疗是晚期胰腺癌患者的主要姑息治疗手段，同时也是手术患者术后辅助治疗中不可或缺的环节。因此，亟需开发更多创新型抗肿瘤药物以对抗这一致命疾病。本研究针对一株海洋来源的枯色拟盘多毛孢（Pestalotiopsis neglecta）菌株所提取的二苯甲酮类衍生物（benzophenone derivatives）展开研究，探讨其作为抗增殖先导化合物用于胰腺癌治疗的潜力。通过生物活性导向分离法从枯色拟盘多毛孢的发酵培养物中，共分离得到9个卤代二苯甲酮类衍生物，其中7个为新化合物（1~7），2个为已知化合物（8和9）。借助包括X射线晶体衍射分析在内的波谱学方法，明确了所有化合物的化学结构。以临床常用胰腺癌细胞系PANC-1进行体外活性评价，结果显示化合物2和4在低微摩尔浓度范围内（分别为7.6 μM和7.2 μM）即可抑制细胞增殖并诱导细胞凋亡。机制研究表明，二苯甲酮类衍生物不仅可抑制细胞质中的丝裂原活化蛋白激酶激酶（Mitogen-activated protein kinase kinase, MEK）活性，还能同时阻断细胞质与细胞核内的细胞外调节蛋白激酶（Extracellular signal-regulated kinase, ERK）活性。计算机模拟研究显示，二苯甲酮类衍生物可通过结合MEK的变构口袋来抑制其活性。综上，二苯甲酮类衍生物可作为治疗胰腺癌的新型先导化合物。